Project Summary/Abstract The proposed project will leverage 16 twin samples from the Interplay of Genes and Environments across Studies (IGEMS) Consortium, and incorporate four additional samples, to clarify which modifiable risk factors may be most influential in increasing risk for Alzheimer’s disease and related dementias (AD/ADRD) and at which developmental stages their risks are greatest. The overarching goal of this project is to apply twin models to strengthen or refute causal hypotheses and test gene-environment interplay among modifiable factors for AD/ADRD, considering risk and resilience profiles within and across developmental periods of the lifespan. Given the aging of the populations worldwide, AD/ADRD are expected to show substantial increases over the next few decades, making the proposed study especially timely. We focus on modifiable risk factors in the hope that clarifying the mechanisms and timing of their effects may help to guide prevention and intervention to reduce AD/ADRD. Many of our genetically- and environmentally-informed samples include longitudinal data and polygenic scores (PGS). Drawing from samples in Sweden, Denmark, Australia, and the United States, we will (a) create multi-dimensional risk scores for early life contexts and (b) evaluate PGSs for neurodevelopmental disorders and educational attainment in addition to PGSs for Alzheimer’s disease (AD), AD resilience, and modifiable factors. We will leverage within-between models of twins and siblings of exposures and genetic risk to test causal hypotheses that control for confounding, and explore gene- environment (GE) interplay of modifiable risk factors for AD/ADRD and qualities of resilience to address our aims: (SA1) evaluate mid- and late life physical health and health behavior factors that alter AD/ADRD risk; (SA2) evaluate midlife and late life socioemotional factors that alter AD/ADRD risk; and (SA3) examine how early life risks work together with midlife and late life health and socioemotional factors to influence AD/ADRD risk while also incorporating GE interplay. The proposed research study will extend the life course model of AD/ADRD by implementing a systems-level approach, guided by the NIH disparities framework, to investigate key environmental factors that contribute to social inequities, including multiple early life adversities and risk factors and measuring them at different times. Indeed, we will evaluate how mid- and late life risk act in combination with early life risks and genetics to create differential profiles of AD/ADRD risk across sex, cohorts, and countries. Our novel approach of leveraging both twin and genomic data will provide converging evidence to inform clinical and policy recommendations with regard to the genetic interplay among risk and protective factors that create differential vulnerabilities for AD/ADRD. The IGEMS Consortium is uniquely positioned to advance the study aims using powerful approaches, rich phenotypes, high variability across exposures and socioeconomically diverse samples, and lifespan coverage.

PROJECT NARRATIVE Alzheimer’s disease and related dementias (AD/ADRD) are predicted to increase substantially, yet how early life risks work together with midlife and late-life modifiable factors to alter AD/ADRD risk is unclear. The proposed project will leverage twin and sibling data, with genomic data, to evaluate life course risk and protective factors for AD/ADRD, testing causal hypotheses and gene-environment interplay. Converging evidence from our approaches will inform clinical and policy recommendations regarding life course risk and protective factors that create differential vulnerabilities for AD/ADRD.